In this grant application we want to continue the search for markers causative and predictive of progression from MGUS to myeloma (MM). We previously established a reference cohort of patients in whom we have slides and samples to perform in situ single cell analysis. Since our last grant submission we have developed the expertise and published using the oligo based array comparative genomic hybridization (aCGH). We propose the following aims to better understand the cause of progression of MGUS to MM and to be able to predict better, so that a more appropriate counseling can occur with patients. Ultimately this information will be used for development of novel therapeutics. In Specific Aim 1 we wish to mine the existing genomic data on MM (both anatomic and functional) and to explore the possibility that some of the newfound markers are indeed progression events. We will subtract from these those already present in MGUS. We will test them as predictive markers, studying MGUS slides, and search for associations with existing baseline cytogenetic categories. In Specific Aim 2 we will explore the possibility that myc is a driver event in the progression to MM through a comprehensive genomic approach, including whole genome, high density, tiling aCGH;the tiling centered on myc at 8q24. We postulate that by either cis or trans deregulation, myc abnormalities contribute to the progression of the disease. We have found, using a murine model that introduces myc activation via somatic hypermutation, and by analysis gene expression signatures in MM and MGUS, that myc deregulation is a candidate mechanisms for disease progression. In Specific Aim 3 we wish to provide the long term outcome of patients initially studied by us. We.will monitor patients in a longitudinal fashion and will introduce the long-term outcome data to that already existing in the cohort and also include the novel markers identified in Specific Aim 1. Lastly, in Specific Aim 4 we would like to do a comparative genomic analysis between MM and other mature B-cell malignancies such as mantle cell lymphoma, marginal zone lymphoma and Waldenstrom macroglobulinemia. Mantle cell lymphoma, like MM, shares cyclin D upregulation (usually D1 but also occasionally D2 and D3) as a pathogenic, such as is the case in MM. Marginal zone lymphoma and Waldenstrom macroglobulinemia share the NF-kB activation state that MM has, and,all these tumors have enhanced responsiveness to bortezomib.